Food allergic responses include diverse diseases ranging from acute oral antigen-induced IgE-mediated anaphylaxis to chronic tissue-specific inflammation such as eosinophilic esophagitis (EoE). A common characteristic of these responses is exposure to acidic microenvironments as systemic anaphylaxis may be associated with acidosis and eosinophilic esophageal inflammation is associated with acid exposure from physiological or pathological reflux. We have recently identified a new pathway involved in allergic inflammatory cell function mediated by the proton-sensing G-protein coupled receptor GPR65. Specifically, we identified GPR65 as a nonredundant acid sensor on eosinophils, leading to increased survival of eosinophils in acidic pH. The esophagus is regularly exposed to acid and this may contribute to enhanced eosinophil responses, including survival (and accumulation). Further, our preliminary data suggest expression of GPR65 on mast cells, which are essential for most models of oral antigen-induced anaphylaxis. We now hypothesize that acidic microenvironment and/or GPR65 are involved in allergen-induced responses including experimental EoE and food allergy. Furthermore, we hypothesize that acidity enhances the function of cells involved in these models, including eosinophils and mast cells. We are hopeful that this study will unravel novel molecular mechanisms involved in IgE-mediated inflammation and will help provide a better understanding of the disease. Finally, by identifying a new pathway, this study may present opportunities for new targets in the disease. Food allergic responses include diverse diseases ranging from life-threatening anaphylaxis to chronic eosinophilic esophagitis. A common characteristic of these responses is exposure to acidic microenvironments. This grant will test the role of acidic microenvironment in food allergy. We will also focus on the effect of acidity on mast cells and eosinophils, cells critically important in these diseases.